Treatment of parkinsonism

ABSTRACT

Use of D-2-chloro-6-methyl-8-cyanomethylergoline in treating the Parkinsonian syndrome.

United States Patent 1 Slater [4 1 Sept. 9, 1975 I TREATMENT OF PARKINSONISM [75] Inventor: Irwin II. Slater. Indianapolis. Ind.

[73] Assignee: Eli Lilly and Company. Indianapolis,

, Ind.

221 Filed: Aug. 8, 1974 2] Appl. No.: 495,613

UNITED STATES PATENTS 3,732.23! 5/ I 973 Scmonsky 424/26I FOREIGN PATENTS OR APPLICATIONS l,0()5.88() 9/1965 United Kingdom 424/26! OTHER PUBLICATIONS Clemens ct 21L, Endocrinology, 1 17] I974).

Primary E.\mi|ir'|er'-StanIey J. Friedman Attorney, Agent, or Firm.|ames L. Rowe; Everet F. Smith 5 7 ABSTRACT Use of D-2-chl0ro-6-methyl-8-cyan0methylerg0line in treating the Parkinsonian syndrome.

2 Claims. No Drawings TREATMENT OF PARKINSONISM Background of the Invention During the late 18 th century, James Parkinson, a British physician, first described the disease, known commonly as paralysis agitans or shaking palsy, which has come to bear his name. Parkinson s disease is characterized by tremor, muscular rigidity and loss of postural reflexes. The disease usually progresses slowly with intervals of to years elapsing before the symptoms cause incapacity. The terms Parkinsonism and the Parkinsonian syndrome include not only Parkinsons disease but also drug-induced Parkinsonism and postencephalitic Parkinsonism. Treatment of Parkinsonism involves symptomatic, supportive and palliative therapy. Parkinsons disease has been treated with various anticholinergic agents which have a greater beneficial effect on rigidity and akinesia than on tremor. More recently l-dopa (l-dihydroxyphenylalanine) has been used because of the finding that there is an altered catecholamine content in the brains of patients afflicted with Parkinsonism. It has also been suggested that monoamineoxidase inhibitors be used to retard the degradation of cerebral catechol amines. The use of l-dopa and of mono-amineoxidase inhibitors are both designed to increase the level of 1- dopamine in the brain and hopefully to alleviate the symptons of Parkinsonism. It has also been suggested by Corrodi and coworkers that certain ergot derivatives, such as the naturally occurring alkaloid, ergococnine, are direct dopamine receptor stimulants of long duration and may therefore prove to be of value in the treatment of Parkinsons disease [see J. Pharm. Pizarmac., 409 (1973)]. Johnson et al. in Experentia, 29 763 (1973) discuss the evidence of Corrodi et al. that ergocornine and 2-bromo-a-ergokryptine stimulate dopamine receptors and extend their observations to other ergot alkaloids. Trever W. Stone writing in Brain Research, 72, 177 (1974) verified the above experiments and produced further evidence that ergot alkaloids have a dopamine receptor stimulating action.

D-2-chloro-6-methyl-8-cyanomethyl-ergoline is reported by Clemens et al., Endocrinology, 94, l 171 (1974) to be a prolactin inhibitor.

Summary of the Invention This invention provides a process for the treatment of Parkinsonism which comprises administering to a human suffering from Parkinsonism and in need of such treatment from 2-10 mg. per day of D-2-chloro-6- methyl-8-cyanomethylergoline or a pharmaceutically acceptable salt thereof formed with a non-toxic acid. Pharmaceutically acceptable salts useful in the process of this invention include sulfates, such as sulfate, pyrosulfate, and bisulfate; sulfites, such as sulfite and bisulfite; nitrate; phosphates, such as phosphate, monohydrogenphosphate, dihydrogenphosphate, mctaphosphate and pyrophosphate; halides, such as chloride, bromide and iodide; C C aliphatic carboxylates, such as acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate and propiolate; C -C aliphatic dicarboxylates, such as oxalate. malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l ,4-dioate and hexyne-l ,6-dioate;

benzoates, such as benzoate. chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate; phthalates, such as phthalate and terephthalate; arylsulfonates, such as toluenesulfonate, benzenesulfonate, naphthalenesulfonate, p-chlorobenzenesulfonate and xylenesulfonate; citrate; C C B-hy' droxy-alkanoates, such as lactate, B-hydroxybutyrate and glycollate; C -C a-hydroxyalkanedioates, such as malate and tartrate; and C -C alkylsulfonates, such as mcthanesulfonate and propanesulfonate.

D-2-chloro6-methyl-8-cyanomethylergoline is prepared by the action of N-chlorosuccinimide or other halogenating agent containing a positive chlorine upon D-6-methyl-8-cyanomethylergoline furnished by the procedure of Semonsky et al., C011. Czech. Chem. Commun., 33, 577 (1968). The compound, preferably in the form of the methane sulfonate salt, is formulated for administration to patients suffering from Parkinsonism conveniently in telescoping gelatin capsules containing 2.0 mg. of base per capsule. A typical formulation contains 2.0 mg. of the compound and 218 mg. of U.S.P. starch per capsule or 2 mg. of compound and 208 mg. of cellulose with sodium carboxymethyl cellulose (C.M.C.) per capsule. Other useful formulations include one in which a mixture of 1 mg. of D-Z-chloro- 6-methyl-8-cyanomethylergo1ine methane sulfonate and 219 mg. of U.S.P. starch are contained in each capsule or in which a mixture of 5 mg. of the same salt and 215 mg. of U.S.P. starch are contained in each capsule. The formulations are prepared by thoroughly mixing the salt and starch (or cellulose containing sodium carboxymethyl cellulose) in the ratios necessary to give the above quantities. The mixture is then loaded into capsules so that each capsule contains 200 total miligrams of mixture where starch is the diluant or 210 total miligrams of mixture where cellulose plus sodium C.M.C. is the diluant. The compound in the form of the methane sulfonate salt or other pharmaceutically acceptable salt can be mixed with other diluants and loaded into telescoping gelatin capsules, or a binder can be added and the mixture pressed into tablets containing l, 2 or 5 mg. of base (regardless of the salt used). The compound can also be administered as a solution or as an aqueous suspension in accordance with standard practices of the art.

In carrying out the novel process of this invention, a patient suffering from Parkinsonism may be given a single capsule containing 1 mg. of base per day; capsules containing 2 mg. of base, three or four times per day; capsules containing 5 mg. of base, twice a day; etc. For the average patient, I have found that 2 mg. of base administered four times a day is a sufficient dosage to relieve the symptoms of Parkinsonism.

I claim:

1. The process for the treatment of Parkinsonism which comprises administering to a human suffering from Parkinsonism and in need of such treatment from 210 mg. per day orally of D-2-chloro-6-methyl-8 cyanomethylergoline or a pharmaceutically acceptable salt thereof formed with a non-toxic acid.

2. The process according to claim 1 in which the methane sulfonate is the pharmaceutically acceptable salt employed. 

1. THE PROCESS FOR THE TREATMENT OF PARKINSONISM WHICH COMPRISES ADMINISTERING TO A HUMAN SUFFERING FROM PARKINSONISM AND IN NEED OF SUCH TREATMENT FROM 2-10MG. PER DAY ORALLY OF D-2-CHLORO-6-METHYL-8-CYANOMETHYLERGOLIE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF FORMED WITH A NONTOXIC ACID.
 2. The process according to claim 1 in which the methane sulfonate is the pharmaceutically acceptable salt employed. 